Schizophrenia (SZ) is characterized by high heritability (~80%) and elevated sibling recurrence (;s ~ 10), yet the identification of susceptibility genes has proven extremely challenging. This application entitled "Common and Rare Genetic Factors in an Ethnically Homogeneous Schizophrenia Cohort" is in response to the NIMH Grand Opportunity area Genomic Profiling of Mental Disorders. In this proposal, we aim to perform a genomewide association study (GWAS), followed by extensive next-generation resequencing (Illumina/Solexa technology), in a large (n=4000) cohort of Ashkenazi Jewish patients with schizophrenia and well-matched Ashkenazi controls. All DNA has already been collected and is immediately ready for genotyping. The Ashkenazi Jewish population, derived from a limited number of founders, may be enriched for a subset of common and/or rare susceptibility alleles, which may therefore have higher odds ratios than those detected by previous studies. Matching funds from private donors will permit high-quality GWAS to be performed at substantially reduced cost to NIH. GWAS will use the new Illumina HumanOmni1-Quad BeadChip, which may permit identification of novel risk variants (including copy number variants and rare variants derived from the 1000 Genomes Project) that have been inaccessible in prior generations of DNA microarrays. In addition to well-powered standard GWAS analysis, GWAS data will be analyzed using a novel haplotype sharing approach. This approach aims to identify extended haplotypes that are shared selectively in case chromosomes, and which may harbor rare variants acting as dominant or recessive risk alleles. Shared haplotypes will then be interrogated by targeted resequencing using the Illumina (formerly Solexa) GA2 platform. The application of a hybrid common+rare variant paradigm to the study of SZ applies a conceptual paradigm that has proven successful in several other complex disorders across multiple biomedical diseases and quantitative traits. Taken together, we believe that this dual approach in a large, well characterized, and ethnically homogenous population will provide informative data on the role of common and rare variants in the genetic architecture of this devastating and disabling disorder, as well as provide an invaluable national resource for future studies of this unique population. The proposed sample will contribute substantially to the ongoing efforts of the Psychiatric GWAS Consortium, of which the PI is a member, and which will serve as a source for replication and validation of results. PUBLIC HEALTH RELEVANCE: Schizophrenia (SZ) constitutes the fifth leading cause of disability in the US. Although strongly heritable, specific genetic risk factors remain unclear. We aim to use state-of-the-art genotyping and resequencing technology in a large, ethnically homogeneous cohort of SZ cases and controls. Findings will create new opportunities for diagnosis and prediction of schizophrenia, and for understanding its biology.